CHAPTER 6

TOXICOLOGY

Toxicology: Topics Cover

• The way toxicants enter biological organism

• The effect of toxicants on biological organism

• The way toxicants are eliminated from biological organism

Fundamental principle of toxicology

“There are no harmless substance, only harmless ways of using substances”

Definition of toxicology

“A qualitative and quantitative study of the adverse/unpleasant effects

of toxicants on biological organism”

• Toxicants are hazardous materials such as:

a. chemical agentse.g. asbestos

b. physical agents (dusts, fibers, noise, and

radiation)

• Toxicity is a property of toxicant that describe its effect on biological organism.

• Toxic hazards is the likelihood/probability of damageto biological organism based on exposure resulting from the use/transport/handling/storage of the toxicants.

What are Toxicants?

Toxic hazard: Asbestos removal by wearing PPE

Toxic hazard: Corrugated asbestos roof

Industrial Hygiene

• The toxicity however, cannot be changed.

• So we need methods to prevent or reduce the entry of toxicants into biological organism

• Industrial hygiene is the identification, evaluation and control of worker/occupational conditions that cause sickness and injury.

• Toxic hazard can be reduced by the application of appropriate industrial hygiene techniques (Chapter 7).

How toxicant enter biological organism?

• Injection: through cuts or hypodermic needles into the skin, usually result in highest blood level concentration.

• Inhalation: through mouth/nose into the lungs (respiratory system), 2nd highest blood level concentration.

• Ingestion: through mouth into stomach and gastrointestinal tract, 2nd lowest in blood level concentration.

• Dermal absorption: through skin membrane, lowest in blood level concentration, note: however, absorption of phenol could result in death

hypodermic

needles

Entry routes for toxicants and methods of control

Entry route Method of control

Ingestion Enforcement of rules on eating and drinking

Inhalation Proper ventilation, use of respirators, hood, and other PPE

Injection Proper protection clothing, PPE and prpoer disposal

Dermal absorption Proper protection clothing and PPE

Respiratory system

• Upper respiratory

• Lower respiratory

Upper

respiratory

Lower

respiratory

Upper respiratory system

– Consists of Nasal passages (Nose, sinuses), Oral cavity (mouth), pharynx, larynx and trachea.

– Functions: filtering, heating, and humidifying the air.

– Affected by toxicants that are soluble in water.

– These toxicants will react or dissolve in the muscus to form acids or bases.

– E.g. hydrogen halides, oxides, hydroxides, sodium dusts.

Lower respiratory system

– Lungs that contain bronchi tubes and alveoli for gas exchange with blood.

– Toxicants affect the function of alveoli by blocking the transfer of gases or by reaction with alveoli wall to produce corrosive/toxic substances.

– E.g. monomers (acrylonitrile), halides (Chlorine), hydrogen sulfide, methyl cyanide etc.

Respiratory system…cont.

• Effect of dust and insoluble materials– The smaller the dust particles, the deeper it penetrates into

respiratory system

– Particles >5μm are filtered in the upper respiratory system.

– 5μm>Particles>2μm can reach bronchial system

– Particles<1μm can reach the alveoli

How toxicants are eliminated from biological organism?

• Excretion- through kidneys (blood to urine), liver (selectively excrete certain chemicals indigestive tract to bile or emulsify fats), lungs , skin (sweats), hair, nail or other organ

• Detoxification-change the chemical into something less harmful by biotransformation through liver, can also occur in blood, intestinal wall, skin, kidney

• Storage- in fatty tissue. Can create problem when fatty deposits are metabolized and released the toxic (e.g. during reduced food supply). Also store in bone, blood, liver, and kidney.

Note: Massive exposure to hazardous chemical can damage major organs (kidney, lung, liver), hence reduces their ability to excrete.

Known your Kidneys?Your kidneys receive the blood from the renal artery (heart

main blood vessel), process it, return the processed blood

to the body through the renal vein and remove the wastes

and other unwanted substances in the urine. Urine flows

from the kidneys through the ureter to the bladder.

Liver Anatomy

Effects of Toxicant• Irreversible

– Carcinogen - cause cancer

– Mutagen - cause chromosome damage (genetic changes in spermatozoa or ovum cells)

– Teratogen - cause birth defects (deformation of foetus)

• May or may not be irreversible

– Dermatotoxic – affects skin

– Hemotoxic – affects blood

– Hepatotoxic- affects liver

– Nephrotoxic – affects kidneys

– Neurotoxic – affects nervous system

– Pulmonotoxic- affects lungs

• Agent orange (contain dioxin)• To reduce the dense jungle

plants/foliage so that army forces might not use it for cover and to deny them use of crops needed for survival/subsistence -Herbicidal warfare turns ‘mutagenic warfare’

• 78 million liters of Agent orange was sprayed during Vietnam War

Medical Test to Determine Exposure Before Symptoms Appears

• Compare results with a medical baseline results (usually done on new employees before employment)

• Medical test will be conducted periodical (every year).– Respiratory problem (using spirometer): asthma (airflow obstruction),

broncitis (upper respiratory infection), emphysema (over air-inflation of alveoli)

– Nervous system disorder: mental status, motor system reflexes, sensory system

– Skin texture, hair, nail, vascularity (blood vessel)– Blood count (red/white cell, hemoglobin, platelet count)– Kidney (test for quantity and for sugar and proteins in urine)– Liver (through chemical test on urine and blood)

Toxicological Studies

• To quantify the effects of toxicant on target organism (e.g. LD-lethal dose, LC-lethal concentration etc.)

• Usually done on animals (lung, kidney, liver) and the results are extrapolated to human.

• For genetic effect, the study is on single-cell of organism/micro organism.

• Different routes requires different toxicological study.

• Involve identifying,

– The toxicant

– The target/organs or test organism

– The effect or response to be monitored

– The dose range

• Ingestion and injection , mg toxicant/kg of body weight

• Gaseous inhalation, ppm or mg/m3 air.

• Particle inhalation, millions of particle per cubic foot (mppcf) or mg/m3 air.

– The period of the test/timing test (mostly acute toxicity study)

• Acute toxicity, single exposure or series of exposure in a short time.

• Chronic toxicity, multiple exposure over a long period of time. This is difficult to perform.

Toxicological Studies….cont.

Dose or Concentration vs Response

• Toxicological test are done on a target population.• Individual target response different for the same dose

(depends on age, sex, weight, diet, gen health).• The results are statistically analyzed.• The results are reported as,

– LD : lethal dose for ingestion or injection or skin absorption– TD : toxic dose for not lethal but irreversible– ED : effective dose for minor and reversible– LC : lethal concentration for gaseous inhalatione.g. LD50 means lethal dose needed to kill 50% of the

subjects/animal population.

Hodge-Sterner Table for Degree of Toxicity

LD50 per kg ofbody weight

Degree of toxicity Probable lethal dose for70-kg human

<1.0 mg Dangerously toxic A taste

1.0 - 50 mg Seriously toxic A teaspoonful

50 – 500 mg Highly toxic An ounce (or 28 gm)

0.5 – 5 g Moderately toxic A pint (or 1/2 quart)

5 – 15 g Slightly toxic A quart (or 1.13 liter)

> 15 g Extremely low toxicity More than a quart

According CPLHC (classification, packing and labelling of

hazardous chemical) or stated in OSHA 1994

LD50 per kg ofbody weight

Degree of toxicity

<25 mg Very toxic

25 to 200 mg Toxic

200 to 500 mg Harmful

Threshold Limit Value (TLV)• Refer to airborne concentrations that correspond to condition

under which no unpleasant/adverse effects are normally expected during worker’s lifetime.

• The body is able to detoxify and eliminate the agent without any detectable effects/synthom.

• Units:

ppm (by volume), for dust mg/m3 and mppcf (millions of particles per ft3 air)

• The TLV assumes that workers are exposed only during normal eight-hour workday.

Threshold Limit Value (TLV)…cont.

– The American Conference of Governmental Industrial

Hygienists (ACGIH) established 3 different types of TLV

– TLV-TWA (Time-weighted average)

– TLV-STEL (Short-term exposure limit)

– TLV-C (Ceiling limit)

TLV-TWA

• Time-weighted average (TWA) for a normal 8-hour workday or 40-hour work week, to which nearly all workers can be exposed, day after day, without unpleasant/adverse effects.

• PEL (Permissible exposure level) defined by OSHA (USA) generally follow closely TLV-TWA

• More TLV-TWA data are available than TLV-STEL and TLV-C • See Appendix G: Table AG-1 (Hazardous Chemical Data for a

Variety of Chemical Substances) or Table 2.8 (2nd edition: old text book)) for variety of TLV-TWA and PEL for a variety of chemical substances.

• or compare with schedule 1 in USECHH (Use and Standards of Exposure of Chemicals Hazardous to Health-Regulations 2000)

TLV-STEL• Short-term exposure limit (STEL).

The maximum concentration to which workers can be exposed for a period of up to 15 minutes continuously without suffering from,

(1) intolerable irritation

(2) chronic or irreversible tissue change

(3) unconsciousness/narcosis of sufficient degree to increase accident proneness, weaken/impair self-rescue, or materially reduce worker efficiency,

provided that no more than 4 excursions per day are permitted, with at least 60 minutes between exposure periods, and provided that the daily TLV-TWA is not exceeded

• Compare with definition of maximum exposure limit in USECHH in OSHA 1994?

TLV-C

• Ceiling limit : “The concentration that should not be exceeded, even directly/instantaneously”.

• Compare with ceiling limit in schedule 1 in USECHH in OSHA 1994?

Convert mg/m3 to ppm from Appendix G : Table AG-1 (or Text book Table 2.8)

• T is in Kelvin, P is the absolute pressure in atm

• M is the molecular weight in g/g-mol

• For T=25oC and P= 1atm,

Cppm

Concentration in ppm=0.08205T

PM

C(mg / m3)

Cppm

= 0.08205298.15

(1)M

C(mg / m3) 24.46

C(mg / m3)

M

For example, Acetone

24.461780

58.08 749.6ppm

; Where C = 1780 mg/m3

M = 58.08 g/gmol

Case study

• A group of 100 workers is exposed to phosgene(chemical reagent) in two repeated/consecutive periods as follows:

10 ppm for 30 minutes and 1 ppm for 300 minutes.

a) Check whether these exposures exceed the TLV?

b) If so, determine the expected number of fatalities?

a) Appendix G: Table AG-1 (or Table 2.8 old text book) the TLV-TWA for phosgene is 0.1 ppm. So two-consecutive exposure at high concentration for 5½ hrs (330 minutes) is definitely above the TLV-STEL as well.

b) To determine the expected number of deaths, we need a correlation.

• Here , we will use probit (probability unit) correlation.

Solutions

Probit Correlation

P 50 1Y 5

|Y 5 |erf

|Y 5 |

2

If we plot percentage (of workers) affected vs magnitude of exposure (e.g. explosion peak overpressure, exposure to hazardous chemical) we typically get a sigmoid shape response as shown in Figure 2.11 (page 55).

However, it is easier to work with straight line. An example of a straight line plot is shown in Figure 2.12 (page 55).

We do that by converting the percentage (P) to a probit variable (Y) using,

Note - erf is error function (given as: mathematical function found in software programs).

- see Example 2.2, page 54 (how to use formula above).

Probit Correlation …cont.

• The relationship between probit variable Y and the contributing/causative variable (V) is given by:

Y = k1+k2lnV (equation 2-5 in text book)

• Where k1 and k2 are probit parameters from Table 2.5, page 53.

• Table 2.5 provide these parameters and the causative variable (V) for a variety of exposures.

• See Example 2.3 (how to use Table 2-4).

We could then tabulate percentage (P) and probit (Y) as given in Table 2-4 (page 52) for convenience.

Fig. 2.10: Probit transformation of sigmoidal response vs log dose curve into a straight line.

Probit Table 2.4

Table 2.5

Revisit our case study

• For deaths due to phosgene exposure, Table 2.5 gives k1=-19.27 and k2=3.69 and V=ΣCT, where T is time in minutes (30 and 300 minutes) and C is concentration in ppm (10 and 1ppm).

Y=k1+k2lnV

Y=k1+k2lnΣCT=-19.27+3.69ln[10(30)+1(300)]

Y=4.33

Thus, from Table 2-4 give percentage = 25% (20 + 5)

So, expected deaths= 0.25x100 workers = 25 workers

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